CN106963742B - 中药固液胶囊及其制备方法 - Google Patents
中药固液胶囊及其制备方法 Download PDFInfo
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- CN106963742B CN106963742B CN201610975892.6A CN201610975892A CN106963742B CN 106963742 B CN106963742 B CN 106963742B CN 201610975892 A CN201610975892 A CN 201610975892A CN 106963742 B CN106963742 B CN 106963742B
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Abstract
本发明公开了一种中药固液胶囊，它是将固体药物制剂与液体药物制剂填充于胶囊壳中制备而成，其中，固体药物制剂的活性成分为中药的水溶性成分，液体药物制剂的活性成分为中药的脂溶性成分。本发明通过“多态一体化胶囊”这一理念，以中药挥发油或脂肪油为非水溶性活性成分的溶解载体，体现了药辅合一的中药用药思想；将水溶性部位制备成微丸或片剂而填充于胶囊中，形成集多种形态于一体的整合型中药新制剂。该剂型实现了中药的全成分输送，为全面、合理地开发中药提供了一种新的方法。
Description
技术领域
本发明涉及中药固液胶囊及其制备方法，属于医药领域。
背景技术
中药制剂面临的最大问题在于其复杂成分的有效递送。中药成分复杂，理化性质差异大，传统的中药制剂只能承载其中一部分活性成分，往往存在疗效不稳定、显效慢、使用不便的缺陷，严重限制了中药制剂的应用及发展。以丹参为例，其脂溶性成分(丹参酮类)水溶性极差，难以成药；而水溶性成分(酚酸类成分)的跨细胞膜能力非常有限，普通制剂均难有效地实现其全组分的高效输送。因此，利用现代技术，针对中药多成分的不同特点设计不同剂型，，去除中药“粗、大、黑”的缺陷，实现“精、小、美”的整合型中药新制剂，是中药现代化、国际化的重要方向。
液体填充技术在上世纪90年代被应用以来，因其可以赋予产品新的生存和竞争优势，现在已经成为新药研发的一门重要技术。液体硬胶囊是基于液体填充技术，将含药液体或半固体灌装入硬胶囊，进而采用同步封口技术对硬胶囊进行密封得到的新型制剂。液体胶囊口服后，囊壳在目的部位接触体液而迅速崩解，释放出其中的含药“液体”，该液体与消化液迅速乳化、溶出并吸收进入血液循环，由于活性成分以分子状态存在于液体中，因而其吸收更容易、快速，生物利用度更高。液体胶囊无臭无味、不易粘连、携带方便，患者服用依从性良好。此外，液体胶囊生产自动化程度非常高，其成本明显低于软胶囊等制剂，具有利于产业化优势。
然而，中药是在中医理论指导下应用的，其重视整体观、系统论，通过系统化、多靶点和多层次而发挥药效作用。中药的复杂成分总体上可以分为水溶性的和非水溶性成分，普通的液体胶囊可以高效地递送非水溶性的成分，但是对于水溶性的成分则并不适用。因此，亟需提供一种新的中药胶囊，实现水溶性和非水溶性成分的共同给药，从而从整体上发挥中药的药效。
发明内容
本发明的目的在于提供中药固液胶囊及其制备方法。
本发明提供了中药固液胶囊，它是内容物包含固体药物制剂与液体药物制剂的胶囊，其中，固体药物制剂的活性成分为中药的水溶性成分，液体药物制剂的活性成分为中药的脂溶性成分。
以不同中药材为原料制备的中药固液胶囊中，水溶性成分与脂溶性成分、固体药物制剂与液体药物制剂的用量配比不完全相同，不同的中药材按实际提取得到的量制备成固液胶囊。
进一步地，所述的水溶性成分为多糖、多酚、皂苷中一种或两种以上的混合物。
进一步地，所述的水溶性成分经水提或浓度20％v/v以下乙醇水溶液提取得到。
进一步地，所述的脂溶性成分为挥发油、脂肪油、蒽醌、黄酮中一种或两种以上的混合物。
进一步地，所述的脂溶性成分由60％～95％v/v乙醇水溶液提取、水蒸气蒸馏法或二氧化碳超临界萃取法提取得到。
进一步地，所述的固体药物制剂包含下述重量配比的原辅料：中药水溶性成分2～10份、填充剂3～20份。
进一步地，所述的填充剂选自淀粉类、糖类、纤维素类、无机盐类中一种或两种以上的混合物。
进一步地，所述的淀粉类填充剂选自药用淀粉、可压性淀粉或其混合物；所述的糖类填充剂选自乳糖、甘露醇或其混合物；所述的纤维素类填充剂选自微晶纤维素；所述的无机盐类填充剂选自硫酸钙、磷酸氢钙或其混合物。
进一步地，所述的液体药物制剂包含下述重量配比的原辅料：中药脂溶性成分1～8份、油相2～40份、表面活性剂1～10份。
进一步地，所述的油相选自花生油、玉米油、橄榄油、大豆油中一种或两种以上的混合物。
进一步地，所述的表面活性剂选自单月桂酸甘油酯、单硬脂酸甘油酯、司盘、吐温中一种或两种以上的混合物。
进一步地，所述的中药材选自丹参、降香、三七、黄芪、当归、陈皮、甘草中一种或两种以上的混合物。
进一步地，所述的中药材选自丹参、重量配比为1:1的丹参:降香的组合物、重量配比为10:1～10:6的丹参:三七的组合物、重量配比为5:1的黄芪:当归的组合物或者重量配比为3:7～7:3的陈皮:甘草的组合物。
本发明提供了一种所述中药固液胶囊的制备方法，包括以下步骤：取中药材，粉碎，提取其水溶性成分制备成固体药物制剂，提取其脂溶性成分制备成液体药物制剂，填充于胶囊壳中，即得。
进一步地，所述脂溶性成分的提取方法包括如下步骤：
醇提法：加入8～12倍体积量的60～95％v/v乙醇水溶液，回流提取1～3次，每次1～3h；或，
水蒸气蒸馏法：料液比1:8～1:20，冷浸时间为1～3h，提取时间为1～6h；或，
二氧化碳超临界萃取法：萃取温度为35～45℃，萃取压力为10～20Mpa，解析温度为30～35℃，解析压力为5～10℃。
进一步地，所述的醇提法还包括如下步骤：将醇提液浓缩至相对密度0.6～0.9，加入2～5倍体积量水静置沉淀，收集沉淀物，即得。
进一步地，所述水溶性成分的提取方法包括如下步骤：
加入8～12倍体积量水煎煮1～3次，每次1～3h；或，
加入6～12倍体积量浓度20％v/v以下的乙醇水溶液回流提取1～3次，每次1～3h。
进一步地，还包括如下步骤：
向提取液中加入95％v/v乙醇水溶液至终浓度为65％～85％v/v，静置沉淀，过滤，浓缩滤液，即得；或，
提取液浓缩后经大孔吸附树脂纯化：上样量与树脂质量比为1:2～1:6，用1～4倍树脂床体积的水洗脱，用1～4倍树脂床体积60～80％v/v乙醇水溶液进行洗脱，收集乙醇洗脱液，浓缩，即得。
进一步地，将所述的固体药物制剂进行包衣。所述包衣包括肠包衣或其他保护，以保证药片稳定性和药物活性成分的释放性能。
本发明中所有相对密度均在55～60℃范围内测得。
本发明将中药水溶性部位制备成微丸、片剂等固体制剂，将脂溶性成分制备成乳剂等液体制剂，两者共同填充于胶囊中，形成集多种形态于一体的整合型中药新制剂。该剂型实现了中药的全成分输送，而且功效实验表明，该剂型的疗效非常优良，为临床使用提供了一种疗效优良的新剂型，也为全面、合理地开发中药提供了一种新的方法。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
实施例1丹参固液胶囊的制备
A.称取丹参饮片原料，切断后粉碎成粗粉；
B.将步骤A中的药材加入8～12倍体积量60～95％v/v乙醇水溶液回流1～3小时，过滤，将滤液浓缩至相对密度1.1～1.3，即得脂溶性成分；
C.向步骤B药渣中加入8～12倍体积量水煎煮1～3小时，过滤，合并滤液，加入95％v/v乙醇水溶液至终浓度为65％～85％v/v，静置沉淀，过滤，将滤液浓缩至相对密度为1.05～1.5的清膏，即得水溶性成分；
D.将步骤C清膏与0.6～1.8倍重量的微晶纤维素采用等量递加法混合，以5～15％w/w聚维酮乙醇溶液作为粘合剂制备软材料，制粒，压制成重量为0.05～0.3g的素片；将素片采用滚转包衣法进行包衣，温度为35～40℃，包衣液(重量组成为羟丙基甲基纤维素8～15％，羧甲基淀粉钠0.5～1％，滑石粉1～2％，余量为水)用量为0.02～0.1重量份，得到药物小片；
E.向步骤B脂溶性成分中加入2～10倍量大豆油，0.1～0.5倍量吐温80以及0.1～0.5倍量维生素E，于50～70℃搅拌混合均匀，得到载药液体；
F.通过灌装机将步骤D经包衣的药物小片和步骤E制备的载药液体同步灌装到空心硬胶囊中，待内容物气体稳定后用明胶线上封口，将封闭的胶囊干燥，包装，即得。
实施例2丹参-降香固液胶囊的制备
A.按照中药配伍的处方量比例为丹参、降香各一份，称取丹参、降香两味中药材并粉碎；
B.将步骤A中降香药材提取挥发油，和含有表面活性剂的食用油搅拌混合，得到油溶性药液；所述挥发油提取法为超临界流体萃取法，其中萃取釜温度为40-60℃，压力20～30Mpa；CO2流量为13～30L/h左右，萃取时间2～4h；
C.将步骤A中丹参药材和步骤B中降香药渣用浓度20％v/v以下的乙醇水溶液回流提取1～3小时，浓缩成稠膏，加入填充剂制粒、过筛、压片，得到药物小片；
D.将步骤B中油溶性药液，加入步骤C中小片，通过液体胶囊灌装机灌装到空心液体硬胶囊中，待内容物气体稳定后用明胶线上封口，将封闭的胶囊干燥，包装，即得。
实施例3丹参-三七固液胶囊的制备
A.按照丹参、三七处方比例(10:1～10:6)，称取丹参、三七两味中药材，丹参粉碎为粗粉，三七粉碎为细粉；
B.将步骤A中丹参药材用60～95％乙醇回流1～3小时提取脂溶性部位，和含有表面活性剂的食用油搅拌混合，得到油溶性药液；
C.将步骤B中丹参药渣用水煎煮1～3小时，浓缩成稠膏，加入步骤A中三七细粉，加入适当填充剂制粒、过筛、压片，得到药物小片；
D.将步骤B中油溶性药液，加入步骤C中小片，通过液体胶囊灌装机灌装到空心液体硬胶囊中，待内容物气体稳定后用明胶线上封口，将封闭的胶囊干燥，包装，即得。
实施例4黄芪-当归固液胶囊的制备
A.按照中药配伍的处方量比例为黄芪、当归(5:1)，称取黄芪、当归两味中药材并粉碎；
B.将步骤A中当归药材提取挥发油，和含有表面活性剂的食用油搅拌混合，得到油溶性药液；
C.将步骤A中黄芪药材和步骤B中当归药渣用8～16倍水煎煮1～3小时，浓缩成稠膏，加入填充剂制粒、过筛、压片，得到药物小片；
D.将步骤B中油溶性药液，加入步骤C中小片，通过液体胶囊灌装机灌装到空心液体硬胶囊中，待内容物气体稳定后用明胶线上封口，将封闭的胶囊干燥，包装，即得。
实施例5陈皮-甘草固液胶囊的制备
A.按照陈皮300～700重量份，甘草300～700重量份，称取陈皮、甘草两味中药材并粉碎；
B.将步骤A中陈皮药材提取挥发油，和含有表面活性剂的食用油搅拌混合，得到油溶性药液；
C.将步骤A中甘草药材和步骤B中陈皮药渣用6～12倍浓度20％v/v以下的乙醇水溶液煎煮1～3小时，浓缩成稠膏，加入填充剂制粒、过筛、压片，得到药物小片；
D.将步骤B中油溶性药液，加入步骤C中小片，通过液体胶囊灌装机灌装到空心液体硬胶囊中，待内容物气体稳定后用明胶线上封口，将封闭的胶囊干燥，包装，即得。
以下通过药效实验证明本发明的有益效果。
实验例1丹参固液胶囊降血脂药效评价
1.造模及给药
雄性Wistar大鼠，适应性饲养1周后，随机分为正常对照组、模型组、辛伐他丁组、丹参水溶性组分、丹参脂溶性组分、水溶+脂溶混合溶液组、固液胶囊组，每组5只。每组大鼠均自由摄水，正常对照组给予基础饲料，其余5组给予高脂饲料(含88.8％基础饲料、10％猪油、1％胆固醇、0.2％甲基硫氧嘧啶)，连续饲喂5周。从实验第6周起，各组大鼠仍如前法饲喂，正常对照组、模型组用生理盐水1ml灌胃；丹参水溶性组给予根据实施例1制备的丹参水溶性成分，剂量为0.1g/(kg·d)，丹参脂溶性组给予根据实施例1制备的丹参脂溶性成分，剂量为0.1g/(kg·d)，混合溶液组给予根据实施例1制备的丹参水溶性成分+脂溶性成分的混合物，剂量为0.2g/(kg·d)，固液胶囊组给予根据实施例1制备的丹参固液胶囊，剂量为0.2g/(kg·d)，灌胃各1ml，辛伐他丁给予5mg/(kg·d)灌胃1ml。各组大鼠均连续灌胃4周，于末次灌胃后处死，取血并进行相应指标检测。
2.生化指标测定
大鼠末次给药后，禁食不禁水12h后采血(未抗凝)，3000r/min离心10min,分离出血清，24h内以全自动生化分析仪检测大鼠血清中HDL-C、LDL-C、TC和TG的含量。
3.实验结果
表1丹参组分对高血脂模型大鼠血清生化指标的影响
▲与模型组对比，P<0.05
与正常对照组相比，模型组大鼠血清HDL-C含量显著减少，TG、LDL-C、TC含量显著增加(p<0.05)。与模型组比较，丹参水溶性组分大鼠血清指标未见显著差异；混合溶液组大鼠HDL-C含量增加，其他指标未见变化；丹参脂溶性组分和固液胶囊组大鼠血清指标HDL-C含量增加，LDL-C、TC和TG含量显著减少，且固液胶囊组大鼠效果优于单独的丹参脂溶性组分。
上述结果表明，丹参脂溶性部位为降血脂的主要活性部位，配伍丹参水溶性组分可增强其降脂作用，表现出协同增效作用。
与将丹参水溶性、脂溶性成分直接混合相比，本发明丹参固液一体化胶囊降低LDL-C、TC和TG含量的效果明显更优，表明该剂型能够很好地弥补丹参脂溶性成分水溶性极差，难以成药以及水溶性成分跨细胞膜能力有限的缺陷，实现丹参全成分的高效输送。
综上，本发明将中药水溶性部位制备成微丸、片剂等固体制剂，将脂溶性成分制备成乳剂等液体制剂，两者共同填充于胶囊中，形成集多种形态于一体的整合型中药新制剂。该剂型实现了中药的全成分输送，而且功效实验表明，该剂型的疗效非常优良，为临床使用提供了一种疗效优良的新剂型，也为全面、合理地开发中药提供了一种新的方法。
Claims (2)
1.中药丹参固液胶囊，其特征是：它是内容物包含固体药物制剂与液体药物制剂的胶囊，其中，固体药物制剂的活性成分为中药丹参的水溶性成分，液体药物制剂的活性成分为中药丹参的脂溶性成分；其中，所述的固体药物制剂包含下述重量配比的原辅料：中药丹参水溶性成分2～10份、填充剂3～20份；所述的液体药物制剂包含下述重量配比的原辅料：中药丹参脂溶性成分1～8份、油相2～40份、表面活性剂1～10份；
所述的丹参固液胶囊由以下方法制备：A.称取丹参饮片原料，切断后粉碎成粗粉；B.将步骤A中的药材加入8～12倍体积量60～95％v/v乙醇水溶液回流1～3小时，过滤，将滤液浓缩至相对密度1.1～1.3，即得脂溶性成分；C.向步骤B药渣中加入8～12倍体积量水煎煮1～3小时，过滤，合并滤液，加入95％v/v乙醇水溶液至终浓度为65％～85％v/v，静置沉淀，过滤，将滤液浓缩至相对密度为1.05～1.5的清膏，即得水溶性成分；D.将步骤C清膏与0.6～1.8倍重量的微晶纤维素采用等量递加法混合，以5～15％w/w聚维酮乙醇溶液作为粘合剂制备软材料，制粒，压制成重量为0.05～0.3g的素片；将素片采用滚转包衣法进行包衣，温度为35～40℃，包衣液用量为0.02～0.1重量份，得到药物小片，包衣液的重量组成为羟丙基甲基纤维素8～15％，羧甲基淀粉钠0.5～1％，滑石粉1～2％，余量为水；E.向步骤B脂溶性成分中加入2～10倍量大豆油，0.1～0.5倍量吐温80以及0.1～0.5倍量维生素E，于50～70℃搅拌混合均匀，得到载药液体；F.通过灌装机将步骤D经包衣的药物小片和步骤E制备的载药液体同步灌装到空心硬胶囊中，待内容物气体稳定后用明胶线上封口，将封闭的胶囊干燥，包装，即得。
2.权利要求1所述的中药丹参固液胶囊的制备方法，其特征是包括如下步骤：A.称取丹参饮片原料，切断后粉碎成粗粉；B.将步骤A中的药材加入8～12倍体积量60～95％v/v乙醇水溶液回流1～3小时，过滤，将滤液浓缩至相对密度1.1～1.3，即得脂溶性成分；C.向步骤B药渣中加入8～12倍体积量水煎煮1～3小时，过滤，合并滤液，加入95％v/v乙醇水溶液至终浓度为65％～85％v/v，静置沉淀，过滤，将滤液浓缩至相对密度为1.05～1.5的清膏，即得水溶性成分；D.将步骤C清膏与0.6～1.8倍重量的微晶纤维素采用等量递加法混合，以5～15％w/w聚维酮乙醇溶液作为粘合剂制备软材料，制粒，压制成重量为0.05～0.3g的素片；将素片采用滚转包衣法进行包衣，温度为35～40℃，包衣液用量为0.02～0.1重量份，得到药物小片，包衣液的重量组成为羟丙基甲基纤维素8～15％，羧甲基淀粉钠0.5～1％，滑石粉1～2％，余量为水；E.向步骤B脂溶性成分中加入2～10倍量大豆油，0.1～0.5倍量吐温80以及0.1～0.5倍量维生素E，于50～70℃搅拌混合均匀，得到载药液体；F.通过灌装机将步骤D经包衣的药物小片和步骤E制备的载药液体同步灌装到空心硬胶囊中，待内容物气体稳定后用明胶线上封口，将封闭的胶囊干燥，包装，即得。
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